The present invention, in some embodiments thereof, relates to peptides and use thereof in the treatment of large cell lung cancer.
Despite advances in surgery, chemotherapy and radiotherapy over the last decades, the death rate from lung cancer remains a global health problem and worldwide, lung cancer is the most common cause of cancer-related death in men and women. The two main types of lung cancer are small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), NSCLC being any type of epithelial lung cancer other than small cell lung carcinoma (SCLC). NSCLC accounts for approximately 85% of all lung cancers. NSCLC is typically divided into adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma histologies, with approximately 10-15% of all NSCLC being large cell lung cancer. Of the non-small cell lung cancers, large cell lung cancer is usually discovered at a later stage. Furthermore, large cell lung cancers tend to be more aggressive and metastasize. The tumor metastasizes into nearby lymph nodes, into the chest wall and into more distant organs, even when the tumor in the lung is relatively small. As diagnosis occurs at an advanced stage, prognosis is typically poor. Large cell lung cancer is insensitive to chemotherapy compared to small cell lung carcinoma. Thus, treatment of NSCLC typically requires multiple treatments including surgical resection, chemotherapeutic agents and/or radiation therapy used both pre-operatively (neoadjuvant chemotherapy) and post-operatively (adjuvant chemotherapy). Among the most widely used chemotherapeutic drugs are cisplatin and paclitaxel.
The chemokine receptor CXCR4 is a G-protein coupled receptor that is expressed in a wide assortment of normal tissues, and plays a fundamental role in fetal development, mobilization of hematopoietic stem cells and trafficking of naive lymphocytes (Rossi and Zlotnik, 2000). The chemokine CXCL12 (also known as stromal-derived factor-1 or SDF-1) is the only natural ligand of CXCR4. CXCL12 is expressed constitutively in a variety of tissues, including lung, liver, bone marrow and lymph nodes.
Binding of CXCL12 to CXCR4 activates a variety of intracellular signal transduction pathways and effector molecules that regulate cell chemotaxis, adhesion, survival and proliferation. For example, the phosphatidyl-inositol-3-kinase pathway and the mitogen-activated protein (MAP) kinase pathways are regulated by CXCL12 and CXCR4.
Various uses of chemokine receptor modulators, including CXCR4 agonists and antagonists, have been described in the art (Princen et al., 2005; Tamamura et al., 2005; U.S. Pat. No. 7,169,750). The bicyclam drug termed AMD3100, originally discovered as an anti-HIV compound, specifically interacts with CXCR4 in an antagonistic manner. Blocking CXCR4 receptor with AMD3100 results in the mobilization of hematopoietic progenitor cells. Other compounds having CXCR4 regulating activity have been described in the art such as in U.S. Publication No. 2007/0167459, U.S. Pat. No. 6,946,445, and U.S. Patent Application Publication No. 2005/0002939. Moreover, various therapeutic applications have been suggested, such as in cancer therapy. T-140 is a 14-residue synthetic peptide developed as a specific CXCR4 antagonist that suppress HIV-1 (X4-HIV-1) entry to T cells through specific binding to CXCR4 (Tamamura et al., 1998). Subsequently, peptide analogs of T-140 were developed as specific CXCR4 antagonist peptides with inhibitory activity at nanomolar levels (see Tamamura et al., 2003, WO 2002/020561 and WO 2004/020462, WO 2004/087068, WO 00/09152, US 2002/0156034, and WO 2004/024178).
WO 2004/087068 discloses antagonists of chemokine receptors, particularly the CXCR4 receptor, and methods of their use, for example, in the treatment, prevention or diagnosis of cancer. The '068 publication discloses that exemplary CXCR4 peptide antagonists include T140 and derivatives of T140, and that the pathology includes cancer such as breast, brain, pancreatic, ovarian, prostate, kidney, and non-small lung cancer.
WO 00/09152 discloses a variety of therapeutic uses for CXCR4 antagonists such as in the treatment of cancer.
WO 2004/024178 discloses the use of a chemokine receptor antagonist as a ligand for the CXCR4 receptor for the apoptosis-inducing treatment and/or the prevention of the metastatic spread of cancer cells in a patient.
U.S. Publication No. 2002/0156034 discloses the use of CXCR4 antagonists for the treatment of hematopoietic cells such as in cancer.
WO 2002/020561 discloses peptide analogs and derivatives of T-140. The '561 publication demonstrates that the claimed peptides are potent CXCR4 inhibitors, manifesting high anti-HIV virus activity and low cytotoxicity.
WO 2004/020462 discloses additional novel peptide analogs and derivatives of T-140, including 4F-benzoyl-TN14003. The '462 publication further discloses preventive and therapeutic compositions and methods of using same utilizing T-140 analogs for the treatment of cancer, such as lung cancer.
Various therapeutic applications for 4F-benzoyl-TN14003 analogs and derivatives have been recently suggested. Some are described in the following related art.
WO 08/075369 is directed to therapeutic uses of T-140 analog peptides and compositions comprising same. Particularly, the '369 publication provides compositions and methods for providing improved bone marrow transplantation and in the treatment of other conditions wherein bone marrow depletion or suppression is involved.
WO 08/075370 is directed to novel therapeutic uses of T-140 analog peptides, compositions comprising same, and use thereof useful in cancer therapy.
WO 08/075371 is directed to novel therapeutic uses of T-140 analog peptides, compositions comprising same, and use thereof useful for immunomodulation.
WO 10/146578 provides compositions comprising T-140 analog peptides and methods of use thereof, specifically for providing improved platelet levels useful in the treatment and prevention of thrombocytopenia, for controlling bleeding and for inducing or modulating haemostasis.
WO 10/146584 discloses novel polypeptides comprising a chemokine-binding peptide and an Fc fragment. According to the '584 publication the polypeptides are capable of binding to certain chemokines so as to modulate their activity, and are therefore useful in modulating in vivo chemokine-dependent processes such as inflammation, autoimmunity and cancer.
Avniel et al. (Avniel et al., 2006) discloses that blocking the CXCR4/CXCL12 axis by a T-140 analog resulted in a significant reduction in eosinophil accumulation in the dermis and improved epithelialization, thus significantly improving skin recovery after burns.